Responsive neurostimulation for the treatment of chronic cardiac dysfunction

ABSTRACT

Systems and methods are provided for delivering neurostimulation therapies to patients for treating chronic heart failure. A neural fulcrum zone is identified and ongoing neurostimulation therapy is delivered within the neural fulcrum zone. The implanted stimulation device includes a physiological sensor for monitoring the patient&#39;s response to the neurostimulation therapy on an ambulatory basis over extended periods of time and a control system for adjusting stimulation parameters to maintain stimulation in the neural fulcrum zone based on detected changes in the physiological response to stimulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/805,062, filed Nov. 6, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/267,922, filed Sep. 16, 2016, now U.S. Pat. No.9,808,626, which is a continuation of U.S. patent application Ser. No.14/861,390, filed Sep. 22, 2015, now U.S. Pat. No. 9,446,237, which is acontinuation of U.S. application Ser. No. 14/271,714, filed May 7, 2014,now U.S. Pat. No. 9,272,143, the entire disclosures of each of which areincorporated herein by reference.

FIELD

This application relates to neuromodulation.

BACKGROUND

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction, and eventual patient death. CHF is pathologicallycharacterized by an elevated neuroexcitatory state and is accompanied byphysiological indications of impaired arterial and cardiopulmonarybaroreflex function with reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF. Forinstance, VNS has been demonstrated in canine studies as efficacious insimulated treatment of AF and heart failure, such as described in Zhanget al., “Chronic Vagus Nerve Stimulation Improves Autonomic Control andAttenuates Systemic Inflammation and Heart Failure Progression in aCanine High-Rate Pacing Model,” Circ Heart Fail 2009, 2, pp. 692-699(Sep. 22, 2009), the disclosure of which is incorporated by reference.The results of a multi-center open-label phase II study in which chronicVNS was utilized for CHF patients with severe systolic dysfunction isdescribed in De Ferrari et al., “Chronic Vagus Nerve Stimulation: A Newand Promising Therapeutic Approach for Chronic Heart Failure,” EuropeanHeart Journal, 32, pp. 847-855 (Oct. 28, 2010).

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under the control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's sideeffect threshold gradually increases, allowing for an increase inintensity during subsequent titration sessions.

Conventional general therapeutic alteration of cardiac vagal efferentactivation through electrical stimulation targets only the efferentnerves of the parasympathetic nervous system, such as described inSabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,”Heart Fail. Rev., 16:171-178 (2011), the disclosure of which isincorporated by reference. The Sabbah paper discusses canine studiesusing a vagus nerve stimulation system, manufactured by BioControlMedical Ltd., Yehud, Israel, which includes an electrical pulsegenerator, right ventricular endocardial sensing lead, and right vagusnerve cuff stimulation lead. The sensing lead enables stimulation of theright vagus nerve in a highly specific manner, which includesclosed-loop synchronization of the vagus nerve stimulation pulse to thecardiac cycle. An asymmetric tri-polar nerve cuff electrode is implantedon the right vagus nerve at the mid-cervical position. The electrodeprovides cathodic induction of action potentials while simultaneouslyapplying asymmetric anodal block that leads to preferential activationof vagal efferent fibers. Electrical stimulation of the right cervicalvagus nerve is delivered only when heart rate is above a presetthreshold. Stimulation is provided at an intensity intended to reducebasal heart rate by ten percent by preferential stimulation of efferentvagus nerve fibers leading to the heart while blocking afferent neuralimpulses to the brain. Although effective in partially restoringbaroreflex sensitivity, increasing left ventricular ejection fraction,and decreasing left ventricular end diastolic and end systolic volumes,a portion of the therapeutic benefit is due to incidental recruitment ofafferent parasympathetic nerve fibers in the vagus. Efferent stimulationalone is less effective than bidirectional stimulation at restoringautonomic balance.

Accordingly, a need remains for an approach to efficiently providingneurostimulation therapy, and, in particular, to neurostimulationtherapy for treating chronic cardiac dysfunction and other conditions.

SUMMARY

In accordance with embodiments of the present invention, aneurostimulation system is provided, comprising: an electrode assembly;a neurostimulator coupled to the electrode assembly, saidneurostimulator adapted to deliver a stimulation signal to a patient inthe patient's neural fulcrum zone, said stimulation signal comprising anON time and an OFF time; a physiological sensor configured to acquire aphysiological signal from the patient; and a control system coupled tothe neurostimulator and the physiological sensor. The control system isprogrammed to: monitor a baseline signal acquired by the physiologicalsensor during the OFF time periods of the stimulation signal; monitor aresponse signal acquired by the physiological sensor during the ON timeperiods of the stimulation signal; and in response to the monitoredbaseline signal and the monitored response signal, adjust one or moreparameters of the stimulation signal to deliver the stimulation signalin the patient's neural fulcrum zone.

In accordance with other embodiments of the present, a method ofoperating an implantable medical device (IMD) comprising a physiologicalsensor configured to acquire a physiological signal from the patient,and a neurostimulator coupled to an electrode assembly, saidneurostimulator adapted to deliver a stimulation signal to a patient.The method comprises: activating the neurostimulator to deliver astimulation signal in a patient's neural fulcrum zone, said stimulationsignal comprising an ON time and an OFF time; monitoring a baselinesignal acquired by the physiological sensor during the OFF time periodsof the stimulation signal; monitoring a response signal acquired by thephysiological sensor during the ON time periods of the stimulationsignal; and in response to the monitored baseline signal and themonitored response signal, adjusting one or more parameters of thestimulation signal to deliver the stimulation signal in the patient'sneural fulcrum zone.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 3.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIGS. 8A-8C are illustrative charts reflecting a heart rate response togradually increased stimulation intensity at different frequencies.

FIG. 9 illustrates a method of operating an implantable medical devicecomprising neurostimulator coupled to an electrode assembly.

FIG. 10 is an illustrative chart reflecting a heart rate response togradually increased stimulation intensity delivered by an implanted VNSsystem at two different frequencies.

FIGS. 11A-11B are block diagrams of neurostimulation systems inaccordance with embodiments of the present invention.

FIG. 12 is an illustrative graph indicating monitoring periods duringdelivery of stimulation signals in accordance with embodiments of thepresent invention.

DETAILED DESCRIPTION

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers, and both afferent and efferent fibers. Thesefibers have different diameters and myelination, and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections: efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1) in a male patient 10, in accordance with embodiments of thepresent invention. The VNS provided through the stimulation system 11operates under several mechanisms of action. These mechanisms includeincreasing parasympathetic outflow and inhibiting sympathetic effects byinhibiting norepinephrine release and adrenergic receptor activation.More importantly, VNS triggers the release of the endogenousneurotransmitter acetylcholine and other peptidergic substances into thesynaptic cleft, which has several beneficial anti-arrhythmic,anti-apoptotic, and anti-inflammatory effects as well as beneficialeffects at the level of the central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The stimulating nerve electrode assembly 125, preferablycomprising at least an electrode pair, is conductively connected to thedistal end of an insulated, electrically conductive lead assembly 13 andelectrodes 14. The electrodes 14 may be provided in a variety of forms,such as, e.g., helical electrodes, probe electrodes, cuff electrodes, aswell as other types of electrodes. The implantable vagus stimulationsystem 11 can be remotely accessed following implant through an externalprogrammer, such as the programmer 40 shown in FIG. 3 and described infurther detail below. The programmer 40 can be used by healthcareprofessionals to check and program the neurostimulator 12 afterimplantation in the patient 10. In some embodiments, an external magnetmay provide basic controls, such as described in commonly assigned U.S.Pat. No. 8,600,505, entitled “Implantable Device For FacilitatingControl Of Electrical Stimulation Of Cervical Vagus Nerves For TreatmentOf Chronic Cardiac Dysfunction,” the disclosure of which is incorporatedby reference. For further example, an electromagnetic controller mayenable the patient 10 or healthcare professional to interact with theimplanted neurostimulator 12 to exercise increased control over therapydelivery and suspension, such as described in commonly assigned U.S.Pat. No. 8,571,654, entitled “Vagus Nerve Neurostimulator With MultiplePatient-Selectable Modes For Treating Chronic Cardiac Dysfunction,” thedisclosure of which is incorporated by reference. For further example,an external programmer may communicate with the neurostimulation system11 via other wired or wireless communication methods, such as, e.g.,wireless RF transmission. Together, the implantable vagus stimulationsystem 11 and one or more of the external components form a VNStherapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the neural stimulation is provided as a low-levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively, or in other various combinations. Stimulation may bethrough multimodal application of continuously cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. A study of the relationship between cardiac autonomic nerveactivity and blood pressure changes in ambulatory dogs is described inJ. Hellyer et al., “Autonomic Nerve Activity and Blood Pressure inAmbulatory Dogs,” Heart Rhythm, Vol. 11 (2), pp. 307-313 (February2014). Generally, cervical vagus nerve stimulation results inpropagation of action potentials from the site of stimulation in abi-directional manner. The application of bi-directional propagation inboth afferent and efferent directions of action potentials withinneuronal fibers comprising the cervical vagus nerve improves cardiacautonomic balance. Afferent action potentials propagate toward theparasympathetic nervous system's origin in the medulla in the nucleusambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, aswell as toward the sympathetic nervous system's origin in theintermediolateral cell column of the spinal cord. Efferent actionpotentials propagate toward the heart 17 to activate the components ofthe heart's intrinsic nervous system. Either the left or right vagusnerve 15, 16 can be stimulated by the stimulation system 11. The rightvagus nerve 16 has a moderately lower (approximately 30%) stimulationthreshold than the left vagus nerve 15 for heart rate effects at thesame stimulation frequency and pulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy Demipulse Model 103or AspireSR Model 106 pulse generator, manufactured and sold byCyberonics, Inc., Houston, Tex., although other manufactures and typesof implantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PerenniaDURAModel 303 lead, or PerenniaFLEX Model 304 lead, also manufactured andsold by Cyberonics, Inc., in two sizes based, for example, on a helicalelectrode inner diameter, although other manufactures and types ofsingle-pin receptacle-compatible therapy leads and electrodes could alsobe used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to deliver continuouslycycling, intermittent and periodic ON-OFF cycles of VNS. Such deliveryproduces action potentials in the underlying nerves that propagatebi-directionally, both afferently and efferently.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monofluoride primary battery or arechargeable secondary cell battery. The electronic circuitry 22 may beimplemented using complementary metal oxide semiconductor integratedcircuits that include a microprocessor controller that executes acontrol program according to stored stimulation parameters and timingcycles; a voltage regulator that regulates system power; logic andcontrol circuitry, including a recordable memory 29 within which thestimulation parameters are stored, that controls overall pulse generatorfunction, receives and implements programming commands from the externalprogrammer, or other external source, collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides remote access to the operation of the neurostimulator 12 usingan external programmer, a simple patient magnet, or an electromagneticcontroller. The recordable memory 29 can include both volatile (dynamic)and non-volatile/persistent (static) forms of memory, such as firmwarewithin which the stimulation parameters and timing cycles can be stored.Other electronic circuitry and components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 internally includes a lead connector block (not shown) and aset of screws 26.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an ECG-type electrode.Through the electrode, the patient's heartbeat can be sensed bydetecting ventricular depolarization. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for cardiacphysiological measures, for instance, detection of the P-wave, QRScomplex, and T-wave. The heart rate sensor 31 provides the sensed heartrate to the control and logic circuitry as sensory inputs that can beused to determine the onset or presence of arrhythmias, particularly VT,and/or to monitor and record changes in the patient's heart rate overtime or in response to applied stimulation signals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28. During implantation, the connector pin 28 isguided through the receptacle 25 into the header 24 and securelyfastened in place using the setscrews 26 to electrically couple the leadassembly 13 to the neurostimulator 12. On a distal end, the leadassembly 13 terminates with the electrodes 14, which bifurcates into apair of anodic and cathodic electrodes 62 (as further described infrawith reference to FIG. 4). In one embodiment, the lead connector 27 ismanufactured using silicone and the connector pin 28 is made ofstainless steel, although other suitable materials could be used, aswell. The insulated lead body 13 utilizes a silicone-insulated alloyconductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes. Thepolarity of the electrodes could be configured into a monopolar cathode,a proximal anode and a distal cathode, or a proximal cathode and adistal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters, suchas described in commonly assigned U.S. Pat. Nos. 8,600,505 and8,571,654, cited supra. FIG. 3 is a diagram showing an externalprogrammer 40 for use with the implantable neurostimulator 12 of FIG. 1.The external programmer 40 includes a healthcare provider operableprogramming computer 41 and a programming wand 42. Generally, use of theexternal programmer is restricted to healthcare providers, while morelimited manual control is provided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42, and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smartphone, or other form of computational device. In oneembodiment, the programming computer is a tablet computer that mayoperate under the iOS operating system from Apple Inc., such as the iPadfrom Apple Inc., or may operate under the Android operating system fromGoogle Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd.In an alternative embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC,Windows Mobile, Windows Phone, Windows RT, or Windows operating systems,licensed by Microsoft Corporation, Redmond, Wash., such as the Surfacefrom Microsoft Corporation, the Dell Axim XS and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Calif. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. The programming computer 41 may further beconfigured to receive inputs, such as physiological signals receivedfrom patient sensors (e.g., implanted or external). These sensors may beconfigured to monitor one or more physiological signals, e.g., vitalsigns, such as body temperature, pulse rate, respiration rate, bloodpressure, etc. These sensors may be coupled directly to the programmingcomputer 41 or may be coupled to another instrument or computing devicethat receives the sensor input and transmits the input to theprogramming computer 41. The programming computer 41 may monitor,record, and/or respond to the physiological signals in order toeffectuate stimulation delivery in accordance with embodiments of thepresent invention.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics, and reports on device diagnostics that includepatient identifier, model identifier, serial number, firmware buildnumber, implant date, communication status, output current status,measured current delivered, lead impedance, and battery status. Otherkinds of telemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46,and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand, and a set of input controls 48 enables the programming wand 42 tobe operated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

Preferably, the electrodes 14 are helical and placed on the cervicalvagus nerve 15, 16 at the location below where the superior and inferiorcardiac branches separate from the cervical vagus nerve. FIG. 4 is adiagram showing the helical electrodes 14 provided as on the stimulationlead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16 in situ 50.Although described with reference to a specific manner and orientationof implantation, the specific surgical approach and implantation siteselection particulars may vary, depending upon physician discretion andpatient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a monopolar cathode, aproximal anode and a distal cathode, or a proximal cathode and a distalanode. In addition, an anchor tether 53 is fastened over the lead bodies57, 58 that maintains the position of the helical electrodes on thevagus nerve 61 following implant. In one embodiment, the conductors ofthe electrodes 51, 52 are manufactured using a platinum and iridiumalloy, while the helical materials of the electrodes 51, 52 and theanchor tether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly assigned U.S. Pat. No. 8,630,709, entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7,2011, the disclosure of which is incorporated by reference.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously cycling, intermittent, andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly assignedU.S. Pat. No. 8,577,458, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S.patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. Pat. No.8,918,190, entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, and U.S. Pat.No. 8,918,191, entitled “Implantable Device for Providing ElectricalStimulation of Cervical Vagus Nerves for Treatment of Chronic CardiacDysfunction with Bounded Titration,” Ser. No. 13/314,135, filed on Dec.7, 2011, the disclosures of which are incorporated by reference.Finally, the neurostimulator 12 can be used to counter natural circadiansympathetic surge upon awakening and manage the risk of cardiacarrhythmias during or attendant to sleep, particularly sleep apneicepisodes, such as respectively described in commonly assigned U.S. Pat.No. 8,923,964, entitled “Implantable Neurostimulator-Implemented MethodFor Enhancing Heart Failure Patient Awakening Through Vagus NerveStimulation,” Ser. No. 13/673,811, filed on Nov. 9, 2012, the disclosureof which is incorporated by reference.

The VNS stimulation signal may be delivered as a therapy in amaintenance dose having an intensity that is insufficient to elicitundesirable side effects, such as cardiac arrhythmias. The VNS can bedelivered with a periodic duty cycle in the range of 2% to 89% with apreferred range of around 4% to 36% that is delivered as a low intensitymaintenance dose. Alternatively, the low intensity maintenance dose maycomprise a narrow range approximately at 17.5%, such as around 15% to20%. The selection of duty cycle is a trade-off among competing medicalconsiderations. The duty cycle is determined by dividing the stimulationON time by the sum of the ON and OFF times of the neurostimulator 12during a single ON-OFF cycle. However, the stimulation time may alsoneed to include ramp-up time and ramp-down time, where the stimulationfrequency exceeds a minimum threshold (as further described infra withreference to FIG. 7).

FIG. 5 is a graph 70 showing, by way of example, the relationshipbetween the targeted therapeutic efficacy 73 and the extent of potentialside effects 74 resulting from use of the implantable neurostimulator 12of FIG. 1, after the patient has completed the titration process. Thegraph in FIG. 5 provides an illustration of the failure of increasedstimulation intensity to provide additional therapeutic benefit, oncethe stimulation parameters have reached the neural fulcrum zone, as willbe described in greater detail below with respect to FIG. 8. As shown inFIG. 5, the x-axis represents the duty cycle 71. The duty cycle isdetermined by dividing the stimulation ON time by the sum of the ON andOFF times of the neurostimulator 12 during a single ON-OFF cycle.However, the stimulation time may also include ramp-up time andramp-down time, where the stimulation frequency exceeds a minimumthreshold (as further described infra with reference to FIG. 7). They-axis represents physiological response 72 to VNS therapy. Thephysiological response 72 can be expressed quantitatively for a givenduty cycle 71 as a function of the targeted therapeutic efficacy 73 andthe extent of potential side effects 74, as described infra. The maximumlevel of physiological response 72 (“max”) signifies the highest pointof targeted therapeutic efficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 73 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,antiarrhythmic, antiapoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 73,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 73 steeply increases beginning at around a 5% duty cycle andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents one optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over stimulation time plus inhibition time. The y-axisrepresents therapeutic points 82 reached in operating theneurostimulator 12 at a given duty cycle 81. The optimal duty range 83is a function 84 of the intersection 75 of the targeted therapeuticefficacy 73 and the extent of potential side effects 74. The therapeuticoperating points 82 can be expressed quantitatively for a given dutycycle 81 as a function of the values of the targeted therapeuticefficacy 73 and the extent of potential side effects 74 at their pointof intersection in the graph 70 of FIG. 5. The optimal therapeuticoperating point 85 (“max”) signifies a trade-off that occurs at thepoint of highest targeted therapeutic efficacy 73 in light of lowestpotential side effects 74, and that point will typically be found withinthe range of a 5% to 30% duty cycle 81. Other expressions of duty cyclesand related factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, VNS is delivered in alow-level maintenance dose that uses alternating cycles of stimuliapplication (ON) and stimuli inhibition (OFF) that are tuned to activateboth afferent and efferent pathways. Stimulation results inparasympathetic activation and sympathetic inhibition, both throughcentrally mediated pathways and through efferent activation ofpreganglionic neurons and local circuit neurons. FIG. 7 is a timingdiagram showing, by way of example, a stimulation cycle and aninhibition cycle of VNS 90, as provided by implantable neurostimulator12 of FIG. 1. The stimulation parameters enable the electricalstimulation pulse output by the neurostimulator 12 to be varied by bothamplitude (output current 96) and duration (pulse width 94). The numberof output pulses delivered per second determines the signal frequency93. In one embodiment, a pulse width in the range of 100 to 250 μSecdelivers between 0.02 mA and 50 mA of output current at a signalfrequency of about 10 Hz, although other therapeutic values could beused as appropriate. In general, the stimulation signal delivered to thepatient may be defined by a stimulation parameter set comprising atleast an amplitude, a frequency, a pulse width, and a duty cycle.

In one embodiment, the stimulation time is considered the time periodduring which the neurostimulator 12 is ON and delivering pulses ofstimulation, and the OFF time is considered the time period occurringin-between stimulation times during which the neurostimulator 12 is OFFand inhibited from delivering stimulation.

In another embodiment, as shown in FIG. 7, the neurostimulator 12implements a stimulation time 91 comprising an ON time 92, a ramp-uptime 97, and a ramp-down time 98 that respectively precede and followthe ON time 92. Under this embodiment, the ON time 92 is considered tobe a time during which the neurostimulator 12 is ON and deliveringpulses of stimulation at the full output current 96. Under thisembodiment, the OFF time 95 is considered to comprise the ramp-up time97 and ramp-down time 98, which are used when the stimulation frequencyis at least 10 Hz, although other minimum thresholds could be used, andboth ramp-up and ramp-down times 97, 98 last two seconds, although othertime periods could also be used. The ramp-up time 97 and ramp-down time98 allow the strength of the output current 96 of each output pulse tobe gradually increased and decreased, thereby avoiding deleteriousreflex behavior due to sudden delivery or inhibition of stimulation at aprogrammed intensity.

Therapeutic vagus neural stimulation has been shown to providecardioprotective effects. Although delivered in a maintenance dosehaving an intensity that is insufficient to elicit undesirable sideeffects, such as cardiac arrhythmias, ataxia, coughing, hoarseness,throat irritation, voice alteration, or dyspnea, therapeutic VNS cannevertheless potentially ameliorate pathological tachyarrhythmias insome patients. Although VNS has been shown to decrease defibrillationthreshold, VNS has not been shown to terminate VF in the absence ofdefibrillation. VNS prolongs ventricular action potential duration, somay be effective in terminating VT. In addition, the effect of VNS onthe AV node may be beneficial in patients with AF by slowing conductionto the ventricles and controlling ventricular rate.

Neural Fulcrum Zone

As described above, autonomic regulation therapy results in simultaneouscreation of action potentials that simultaneously propagate away fromthe stimulation site in afferent and efferent directions within axonscomprising the cervical vagus nerve complex. Upon stimulation of thecervical vagus nerve, action potentials propagate away from thestimulation site in two directions: efferently toward the heart andafferently toward the brain. Different parameter settings for theneurostimulator 12 may be adjusted to deliver varying stimulationintensities to the patient. The various stimulation parameter settingsfor current VNS devices include output current amplitude, signalfrequency, pulse width, signal ON time, and signal OFF time.

When delivering neurostimulation therapies to patients, it is generallydesirable to avoid stimulation intensities that result in eitherexcessive tachycardia or excessive bradycardia. However, researchershave typically utilized the patient's heart rate changes as a functionalresponse indicator or surrogate for effective recruitment of nervefibers and engagement of the autonomic nervous system elementsresponsible for regulation of heart rate, which may be indicative oftherapeutic levels of VNS. Some researchers have proposed that heartrate reduction caused by VNS stimulation is itself beneficial to thepatient.

In accordance with embodiments of the present invention, a neuralfulcrum zone is identified, and neurostimulation therapy is deliveredwithin the neural fulcrum zone. This neural fulcrum zone corresponds toa combination of stimulation parameters at which autonomic engagement isachieved but for which a functional response determined by heart ratechange is nullified due to the competing effects of afferently andefferently transmitted action potentials. In this way, thetachycardia-inducing stimulation effects are offset by thebradycardia-inducing effects, thereby minimizing side effects such assignificant heart rate changes while providing a therapeutic level ofstimulation. One method of identifying the neural fulcrum zone is bydelivering a plurality of stimulation signals at a fixed frequency butwith one or more other parameter settings changed so as to graduallyincrease the intensity of the stimulation.

FIGS. 8A-8C provide illustrative charts reflecting the location of theneural fulcrum zone. FIG. 8A is a chart 800 illustrating a heart rateresponse in response to such a gradually increased intensity at a firstfrequency, in accordance with embodiments of the present invention. Inthis chart 800, the x-axis represents the intensity level of thestimulation signal, and the y-axis represents the observed heart ratechange from the patient's baseline basal heart rate observed when nostimulation is delivered. In this example, the stimulation intensity isincreased by increasing the output current amplitude.

A first set 810 of stimulation signals is delivered at a first frequency(e.g., 10 Hz). Initially, as the intensity (e.g., output currentamplitude) is increased, a tachycardia zone 851-1 is observed, duringwhich period, the patient experiences a mild tachycardia. As theintensity continues to be increased for subsequent stimulation signals,the patient's heart rate response begins to decrease and eventuallyenters a bradycardia zone 853-1, in which a bradycardia response isobserved in response to the stimulation signals. As described above, theneural fulcrum zone is a range of stimulation parameters at which thefunctional effects from afferent activation are balanced with ornullified by the functional effects from efferent activation to avoidextreme heart rate changes while providing therapeutic levels ofstimulation. In accordance with some embodiments, the neural fulcrumzone 852-1 can be located by identifying the zone in which the patient'sresponse to stimulation produces either no heart rate change or a mildlydecreased heart rate change (e.g., <5% decrease, or a target number ofbeats per minute). As the intensity of stimulation is further increasedat the fixed first frequency, the patient enters an undesirablebradycardia zone 853-1. In these embodiments, the patient's heart rateresponse is used as an indicator of autonomic engagement. In otherembodiments, other physiological responses may be used to indicate thezone of autonomic engagement at which the propagation of efferent andafferent action potentials are balanced, the neural fulcrum zone.

FIG. 8B is a chart 860 illustrating a heart rate response in response tosuch a gradually increased intensity at two additional frequencies, inaccordance with embodiments of the present invention. In this chart 860,the x-axis and y-axis represent the intensity level of the stimulationsignal and the observed heart rate change, respectively, as in FIG. 8A,and the first set 810 of stimulation signals from FIG. 8A is also shown.

A second set 810 of stimulation signals is delivered at a secondfrequency lower than the first frequency (e.g., 5 Hz). Initially, as theintensity (e.g., output current amplitude) is increased, a tachycardiazone 851-2 is observed, during which period, the patient experiences amild tachycardia. As the intensity continues to be increased forsubsequent stimulation signals, the patient's heart rate response beginsto decrease and eventually enters a bradycardia zone 853-2, in which abradycardia response is observed in response to the stimulation signals.The low frequency of the stimulation signal in the second set 820 ofstimulation signals limits the functional effects of nerve fiberrecruitment and, as a result, the heart response remains relativelylimited. Although this low-frequency stimulation results in minimal sideeffects, the stimulation intensity is too low to result in effectiverecruitment of nerve fibers and engagement of the autonomic nervoussystem. As a result, a therapeutic level of stimulation is notdelivered.

A third set 830 of stimulation signals is delivered at a third frequencyhigher than the first and second frequencies (e.g., 20 Hz). As with thefirst set 810 and second set 820, at lower intensities, the patientfirst experiences a tachycardia zone 851-3. At this higher frequency,the level of increased heart rate is undesirable. As the intensity isfurther increased, the heart rate decreases, similar to the decrease atthe first and second frequencies but at a much higher rate. The patientfirst enters the neural fulcrum zone 852-3 and then the undesirablebradycardia zone 853-3. Because the slope of the curve for the third set830 is much steeper than the second set 820, the region in which thepatient's heart rate response is between 0% and −5% (e.g., the neuralfulcrum zone 852-3) is much narrower than the neural fulcrum zone 852-2for the second set 820. Accordingly, when testing different operationalparameter settings for a patient by increasing the output currentamplitude by incremental steps, it can be more difficult to locate aprogrammable output current amplitude that falls within the neuralfulcrum zone 852-3. When the slope of the heart rate response curve ishigh, the resulting heart rate may overshoot the neural fulcrum zone andcreate a situation in which the functional response transitions from thetachycardia zone 851-3 to the undesirable bradycardia zone 853-3 in asingle step. At that point, the clinician would need to reduce theamplitude by a smaller increment or reduce the stimulation frequency inorder to produce the desired heart rate response for the neural fulcrumzone 852-3.

FIG. 8C is a chart 880 illustrating mean heart rate response surfaces inconscious, normal dogs during 14-second periods of right cervical vagusVNS stimulation ON-time. The heart rate responses shown in z-axisrepresent the percentage heart rate change from the baseline heart rateat various sets of VNS parameters, with the pulse width the pulse widthset at 250 μSec, the pulse amplitude ranging from 0 mA to 3.5 mA(provided by the x-axis) and the pulse frequency ranging from 2 Hz to 20Hz (provided by the y-axis). Curve 890 roughly represents the range ofstimulation amplitude and frequency parameters at which a null response(i.e., 0% heart rate change from baseline) is produced. This nullresponse curve 890 is characterized by the opposition of functionalresponses (e.g., tachycardia and bradycardia) arising from afferent andefferent activation.

FIG. 9 illustrates a method of operating an implantable medical device(IMD) comprising neurostimulator coupled to an electrode assembly. Thismethod can be implemented using, for example, the VNS systems describedabove.

In step 901, the IMD is activated to deliver to the patient a pluralityof stimulation signals at a first frequency (e.g., 2 Hz, as describedabove with respect to FIG. 9). Each of the plurality of stimulationsignals is delivered having at least one operational parameter settingdifferent than the other stimulation signals. For example, as describedabove, the output current amplitude is gradually increased whilemaintaining a fixed frequency. In other embodiments, differentparameters may be adjusted to increase the intensity of stimulation at afixed frequency.

In step 902, the patient's physiological response is monitored. In theexample described above with respect to FIG. 8, the physiologicalresponse being observed is the patient's basal heart rate duringstimulation at the various intensities at the first frequency. Thephysiological response may be measured using an implanted or externalphysiological sensor, such as, e.g., an implanted heart rate monitor 31,as well as other available physiological data, for instance, asderivable from an endocardial electrogram.

In step 903, the neural fulcrum zone for that first frequency isidentified. In the example described above with respect to FIG. 8, theneural fulcrum zone corresponds to the range of stimulation parametersettings that result in a heart rate change of about 0% to about adecrease of 5%. In other embodiments, a different range of target heartrate changes or other physiological responses may be used to identifythe neural fulcrum zone.

In accordance with some embodiments, stimulation at multiple frequenciesmay be delivered to the patient. In step 904, the IMD is activated todeliver to the patient a plurality of stimulation signals at a secondfrequency. In step 905, the patient's physiological response (e.g.,basal heart rate) at the second frequency is observed. In step 906, theneural fulcrum zone for the second frequency is identified. Additionalfrequencies may be delivered, and corresponding neural fulcrum zones maybe identified for those frequencies.

As described in the various embodiments above, neural fulcrum zones maybe identified for a patient. Different neural fulcrum zones may beidentified using different stimulation signal characteristics. Based onthe signal characteristics, the patient's physiological response to thestimulation may be mild with a low slope, as with, for example, thefirst set of stimulation signals 810 at a low frequency, or may beextreme with a large slope, as with, for example, the third set ofstimulation signals 830 at a high frequency. Accordingly, it may beadvantageous to identify a frequency at which the reaction is moderate,producing a moderate slope corresponding to a wide neural fulcrum zonein which therapeutically effective stimulation may be provided to thepatient.

The observation of tachycardia in the tachycardia zone 851-2 andbradycardia in the bradycardia zone 853-2 indicates that the stimulationis engaging the autonomic nervous system, which suggests that atherapeutically effective intensity is being delivered. Typically,clinicians have assumed that stimulation must be delivered at intensitylevels where a significant physiological response is detected. However,by selecting an operational parameter set in the neural fulcrum zone852-2 that lies between the tachycardia 851-2 and the bradycardia zone853-2, the autonomic nervous system may still be engaged without riskingthe undesirable effects of either excessive tachycardia or excessivebradycardia. At certain low frequencies, the bradycardia zone may not bepresent, in which case the neural fulcrum zone 852-2 is located adjacentto the tachycardia zone. While providing stimulation in the neuralfulcrum zone, the autonomic nervous system remains engaged, but thefunctional effects of afferent and efferent activation are sufficientlybalanced so that the heart rate response is nullified or minimized (<5%change). Ongoing stimulation therapy may then be delivered to thepatient at a fixed intensity within the neural fulcrum zone.

Fine Control of Neurostimulation

In accordance with embodiments of the present invention, fine control ofneurostimulation intensity settings may be achieved for locating theneural fulcrum zone. A patient's physiological response to stimulationmay vary depending on stimulation frequency and other stimulationparameters, and may be monitored by a clinician as a parameterindicative of the patient's autonomic balance. In accordance withembodiments of the present invention, one physiological responseindicative of autonomic balance is a heart rate response.

In the embodiment shown in FIG. 8B, the patient's varying heart rateresponse to stimulation at different stimulation frequencies is shown.At low stimulation frequencies, such as the 5 Hz frequency correspondingto the second set 820 of stimulation signals in FIG. 8B, the slope ofthe heart rate response curve is very low, and a step change instimulation intensity results in a small change in cardiac response. Incontrast, at high stimulation frequencies, such as the 20 Hz frequencycorresponding to the third set 830 of stimulation signals in FIG. 8B,the slope of the heart rate response curve is large, particularly in theneural fulcrum zone 852-3, and a step change in stimulation intensityresults in a large change in cardiac response. In accordance withembodiments of the present invention, an understanding of therelationship between the neural fulcrum zone and the stimulationparameters may be used to enable fine control of intensity settings whenattempting to locate the neural fulcrum zone.

FIG. 10 is an illustrative chart reflecting a heart rate response togradually increased stimulation intensity delivered by an implanted VNSsystem at two different frequencies. In this simplified example, theintensity setting along the x-axis comprises the stimulation outputcurrent, a first set 1010 of stimulation signals is delivered at a firstfrequency (e.g., 20 Hz), and a second set 1020 of stimulation signals isdelivered at a second frequency (e.g., 10 Hz).

In various embodiments, the various stimulation parameter settings forthe VNS system are adjusted according to predefined increments. In theexample shown in FIG. 10, adjustments to the stimulation output currentare made in 0.5 mA increments. In other cases, the adjustments to thestimulation output current may be made in different increments, such as,for example, 0.25 mA or 1.0 mA. In some cases, these predefinedincrements may be dictated by hardware or software limitations, such asa VNS pulse generator that can only be adjusted in 0.5 mA increments. Inother cases, the predefined increments may be imposed by themanufacturer or the clinician to improve consistency, simplicity, oradministrative ease.

If the VNS system were used to deliver a continuous range of outputcurrents at the first and second frequencies, the continuous heart rateresponse curves 1010 and 1020 shown in FIG. 10 would be detected.However, in accordance with embodiments of the present invention, theVNS system is configured to deliver stimulation output currents atpredetermined increments of 0.5 mA. As a result, when a first set 1010of stimulation signals is delivered at 20 Hz, four points along theheart rate response curve are detected: 1012-1, 1012-2, 1012-3, and1012-4. The heart rate responses at 1012-1, 1012-2, and 1012-3 detectedat the first three current levels (0.5 mA, 1.0 mA, and 1.5 mA) all fallwithin the tachycardia zone 851-1 for the first frequency. When theoutput current is increased by the predetermined increment of 0.5 mA,the next detected heart rate response at 1012-4 falls in the bradycardiazone 853-1. Because of the steep slope of the heart rate response curvein the neural fulcrum zone 852-1, when increasing the output current bythe predefined 0.5 mA increment, a heart rate response in the neuralfulcrum zone 852-2 is not detected.

When attempting to locate the neural fulcrum for a particular patient,if the detected heart rate response transitions from the tachycardiazone 851-1 to the bradycardia zone 853-1 in response to a singleincrement increase of the intensity setting, it may be desirable to usea different stimulation frequency to locate the neural fulcrum.Accordingly, the stimulation frequency is decreased (e.g., to 10 Hz, asshown in FIG. 10), and a second set 1020 of stimulation signals aredelivered to the patient at the lower frequency. As with the first set1010, the intensity of the stimulation is increased by predefinedincrements (e.g., of 0.5 mA) to provide heart rate response points1022-1, 1022-2, 1022-3, and 1022-4. Unlike the first set 1010, the heartrate response curve for the second frequency has a lower slope, whichprovides a clinician with a finer resolution investigation of the heartrate response curve in the neural fulcrum zone 852-2, even when limitedby the same 0.5 mA predefined increment of output current. As shown inFIG. 10, the first two stimulation signals at 0.5 mA and 1.0 mA resultin heart rate response points 1022-1 and 1022-2, respectively, whichfall within the tachycardia zone 851-2. Increasing the output current to1.5 mA results in heart rate response point 1022-3, which falls squarelywithin the neural fulcrum zone 852-2. If the output current is increasedby another predefined increment to 2.0 mA, a heart rate response point1022-4 falling within the bradycardia zone 853-1 is detected.

As a result, a clinician may determine that the stimulation parametersettings resulting in the heart rate response point 1022-3 correspond tothe neural fulcrum zone. Accordingly, the VNS system may be configuredto chronically deliver stimulation signals corresponding to theidentified neural fulcrum zone to treat chronic cardiac dysfunction.

In some situations, such as that illustrated in the second set 820 ofstimulation signals of FIG. 8B, the stimulation frequency may be so lowthat stimulation signal limits the functional effects of nerve fiberrecruitment, and the heart rate response remains relatively limited.Although this low frequency stimulation results in minimal side effectsand never induces bradycardia, despite increases in the output current,the overall stimulation intensity remains too low to result in effectiverecruitment of nerve fibers and engagement of the autonomic nervoussystem. As a result, a therapeutic level of stimulation is notdelivered. This is illustrated in FIG. 8B by the low slope of the heartrate response to the second set 820 of stimulation signals. Despiteincreases in the output current up to maximum levels tolerable by thepatient, the stimulation signals never reach the level of autonomicengagement.

In accordance with embodiments of the present invention, if incrementalincreases of an intensity setting (e.g., output current) at a firstfrequency do not result in an adequate change in the heart rate, thefrequency of stimulation may be increased to produce a heart rateresponse curve with a larger slope. The output current may be reduced toan initial level (e.g., 0.5 mA), with subsequent stimulation signalsdelivered at incrementally increasing output currents. Aftertransitioning past the tachycardia zone, a stimulation signal deliveredat the higher frequency at one output current level will induce a heartrate response point that falls within the neural fulcrum zone, and asubsequent stimulation signal with a single predefined incrementalincrease in the output current level induces a heart rate response inthe bradycardia zone. The output current level may then be reduced bythe predefined increment to bring the stimulation back into the neuralfulcrum zone.

Dynamic Stimulation Adjustment

In some embodiments described herein, the stimulation parameters may bemanually adjusted by a clinician in order to locate the neural fulcrumzone. In accordance with other embodiments of the present invention,computer-implemented methods are used for monitoring the patient'sresponse to stimulation and dynamically adjusting stimulation parametersin order to locate the neural fulcrum zone. This monitoring and dynamicadjustment may be performed in clinic utilizing an external controlsystem, or it may be automatically performed by an implanted controlsystem coupled to an implanted physiological sensor, such as, forexample, an ECG sensor for monitoring heart rate.

FIG. 11A is a simplified block diagram of an implanted neurostimulationsystem 1100 in accordance with embodiments of the present invention. Theimplanted neurostimulation system 1100 comprises a control system 1102comprising a processor programmed to operate the system 1100, a memory1103, a physiological sensor 1104, and a stimulation subsystem 1106. Thephysiological sensor 1104 may be configured to monitor any of a varietyof patient physiological signals, and the stimulation subsystem 1106 maybe configured to deliver a stimulation signal to the patient. In oneexample, the physiological sensor 1104 comprises an ECG sensor formonitoring heart rate, and the stimulation subsystem 1106 comprises aneurostimulator 12 programmed to deliver ON-OFF cycles of stimulation tothe patient's vagus nerve.

The control system 1102 is programmed to activate the neurostimulator 12to deliver varying stimulation intensities to the patient and to monitorthe physiological signals in response to those stimulation signals.

FIG. 12 is an illustrative graph indicating monitoring periods duringdelivery of stimulation signals in accordance with embodiments of thepresent invention. First, the control system 1102 activates thephysiological sensor 1104 to monitor the patient's heart rate (or otherphysiological signal) during a resting period 1202 in which theneurostimulator 12 is in an OFF time period with no stimulation signalsbeing delivered to the patient. The monitoring heart rate during theresting period 1202 establishes the patient's baseline heart rate.

Next, during the stimulation ON time period 92, the control system 1102activates the physiological sensor 1104 to monitor the patient's heartrate response to the stimulation during a response period 1206. Asdescribed above, the heart rate response during stimulation can be usedto locate the neural fulcrum zone. For example, if tachycardia isdetected, the control system 1102 may be configured to automaticallyincrease the intensity of subsequent stimulation signals in order totravel farther along the response curve described above with respect toFIG. 8B. The control system 1102 may be further programmed to graduallyincrease the stimulation intensity until bradycardia is detected and theneural fulcrum is located.

In accordance with some embodiments, the control system 1102 may beprogrammed to maintain a stimulation parameter setting for a pluralityof cycles, while monitoring the baseline heart rate and heart rateresponse for each stimulation cycle. The control system 1102 may beprogrammed to calculate one or more statistical descriptors (e.g., mean,median, minimum, maximum, etc.) of the baseline heart rates and heartrate responses in order to provide a more accurate measurement of thepatient's response to stimulation by aggregating the multiple responsesto stimulation. In addition, the control system 1102 may store thephysiological measurements in the memory 1103 for performing thesecalculations for later analysis.

In accordance with some embodiments, the control system 1102 may beprogrammed to utilize a delay period 1208 following completion of an ONtime period prior to monitoring the baseline heart rate during restingperiod 1202. This delay period 1208 may comprise, for example, betweenone and five seconds, or more, and may provide the patient's heart witha period of time to return to its baseline heart rate before resumingmonitoring. In accordance with some embodiments, the control system 1102may be programmed to utilize an ON time delay period (not shown)following initiation of an ON time period prior to monitoring the heartrate response during the response period 1206. This ON time delay periodmay comprise, for example, between one and five seconds, or more, andmay provide the patient's heart with a period of time to adjust from thebaseline rate and stabilize at the stimulation response rate beforeinitiating monitoring during the response period 1206. In someembodiments, the physiological sensor 1104 may continuously monitor thepatient's heart rate (or other physiological signal), and the controlsystem 1102 is programmed to locate the heart rate during the particularperiods of interest (e.g., resting period 1202 and response period1206).

The synchronization of the stimulation signal delivery and themonitoring of the patient's heart rate may be advantageously implementedusing control system in communication with both the stimulationsubsystem 1106 and the physiological sensor 1104, such as byincorporating all of these components into a single implantable device.In accordance with other embodiments, the control system may beimplemented in a separate implanted device or in an external programmer1120, as shown in FIG. 11B. The external programmer 1120 in FIG. 11B maybe utilized by a clinician or by the patient for adjusting stimulationparameters. The external programmer 1120 is in wireless communicationwith the implanted medical device 1110, which includes the stimulationsubsystem 1116. In the illustrated embodiment, the physiological sensor1114 is incorporated into the implanted medical device 1110, but inother embodiments, the sensor 1114 may be incorporated into a separateimplanted device, may be provided externally and in communication withthe external programmer 1120, or may be provided as part of the externalprogrammer 1120.

Long-Term Monitoring

In accordance with embodiments of the present invention, the implanteddevice includes a physiological sensor configured to acquire aphysiological signal from the patient and a non-volatile memory forrecording the physiological signals over extended periods of time on anambulatory basis. In some embodiments, the physiological sensorcomprises a heart rate sensor for measuring heart rate variability. Thiscan permit the device to deliver neurostimulation signals to the patienton a chronic basis, while recording the patient's physiological responseto the stimulation outside of the clinic over extended periods of time.The physiological signals may be recorded over periods of time such as,for example, days, weeks, months, or years. The recording of thephysiological signals may be continuous (e.g., 24 hours per day, 7 daysa week), or may be intermittent. In systems where the monitoring andrecording is intermittent, the recording may be performed for anydesired length of time (e.g., minutes, hours, etc.) and at any desiredperiodicity (e.g., during certain periods of the day, once per hour,day, week, month, or other period of interest).

The implanted device may include a communication interface forwirelessly transmitting the recorded physiological signals to anexternal computing device, such as the external programmer describedabove. The recorded signals can then be analyzed, evaluated, orotherwise reviewed by a clinician. As a result, the clinician can setthe stimulation parameters for the patient's implanted device, and thencan review the patient's response to chronic stimulation at thatparameter setting over extended periods of time. The extended ambulatorydata can permit the clinician to adjust or refine the stimulationparameters to achieve the optical therapeutic effect, without beinglimited to the physiological signals of short duration recorded inclinic.

Closed-Loop Neurostimulation

As described above, embodiments of the implanted device may include aphysiological sensor, such as a heart rate sensor, configured to monitora physiological signal from the patient over extended periods of time onan ambulatory basis. In accordance with embodiments of the presentinvention, the implanted device may be configured to adjust stimulationparameters to maintain stimulation in the neural fulcrum zone based ondetected changes in the physiological response to stimulation.

In some embodiments described above, the identification of the neuralfulcrum zone and the programming of the stimulation parameters todeliver stimulation signals in the neural fulcrum zone may be performedin a clinic by a healthcare provider. In some embodiments, the implantedmedical device may be configured to automatically monitor the patient'sphysiological response using an implanted physiological sensor toinitially identify the neural fulcrum zone and set the stimulationparameters to deliver signals in the neural fulcrum zone. In addition,under certain circumstances, the patient's physiological response tothose initial stimulation parameters may change. This change could occuras the stimulation is chronically delivered over an extended period oftime as the patient's body adjusts to the stimulation. Alternatively,this change could occur as a result of other changes in the patient'scondition, such as changes in the patient's medication, disease state,circadian rhythms, or other physiological change.

If the changes in the patient's response to stimulation results in achange in the patient's response curve, the initially identifiedstimulation parameters may no longer deliver stimulation in the neuralfulcrum zone. Therefore, it may be desirable for the implanted medicaldevice to automatically adjust one or more stimulation parameters (e.g.,pulse amplitude) so that subsequent stimulation signals may be deliveredin the neural fulcrum zone. For example, in embodiments described above,where the monitored physiological response is the patient's heart rate,then if tachycardia is later detected in response to stimulation signalsthat had previously resulted in a transition heart rate response, theIMD may be configured to automatically increase the pulse amplitude (orother stimulation parameters) until a transition heart rate response isagain detected. Subsequent stimulation may continue to be deliveredusing the new stimulation parameters until another change in thepatient's physiological response is detected.

In some embodiments, the patients physiological response may besubstantially continuously monitored. In other embodiments, thepatient's physiological response may be monitored on a periodic basis,such as, for example, every minute, hour, day, or other periodic oraperiodic schedule that may be desired in order to provide the desiredmonitoring schedule. In other embodiments, the patient's physiologicalresponse may be monitored in response to a control signal delivered byan external device, such as a control magnet or wireless data signalfrom a programming wand. The external control signal to initiatemonitoring may be delivered when it is desired to monitor thephysiological response when a patient condition is changing, such aswhen the patient is about to take a medication, is about to go to sleep,or has just wakened. In some embodiments, the external control signalmay be used by the patient when an automatically increasing stimulationintensity in response to monitoring physiological signals is causingundesirable side effects. When the IMD receives such a control signal,the IMD may be programmed to automatically reduce the stimulationintensity until the side effects are alleviated (as indicated, forexample, by a subsequent control input).

It will be understood that output current is merely one example of astimulation parameter that may be adjusted in order to identify theneural fulcrum zone. In other embodiments, the stimulation may be variedby adjusting the other intensity parameters, such as, for example, pulsewidth, pulse frequency, and duty cycle.

In various embodiments described above, the patient's heart rateresponse is used as the patient parameter indicative of the patient'sautonomic regulatory function in response to the stimulation forlocating the neural fulcrum zone. In other embodiments, differentpatient parameters may be monitored in conjunction with stimulation,including, for example, other heart rate variability parameters, ECGparameters such as PR interval and QT interval, and non-cardiacparameters such as respiratory rate, pupil diameter, and skinconductance. Increases and decreases in these patient parameters inresponse to changes in stimulation intensity may be used to identify thepatient's neural fulcrum. If the change in the patient parameter inresponse to an incremental increase in a stimulation parameter is toolarge to enable identification of the neural fulcrum zone (e.g., theslope of the response curve is large), the frequency of the stimulationmay be decreased and an additional set of stimulation signals may bedelivered to the patient. At the lower frequency, the slope of theresponse curve will decrease, enabling a finer resolution identificationof the neural fulcrum zone. Conversely, if the change in the patientparameter is too low (e.g., the slope of the response curve is toosmall), the frequency may be increased in order to achieve finerresolution identification of the neural fulcrum zone.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope. Forexample, in various embodiments described above, the stimulation isapplied to the vagus nerve. Alternatively, spinal cord stimulation (SCS)may be used in place of or in addition to vagus nerve stimulation forthe above-described therapies. SCS may utilize stimulating electrodesimplanted in the epidural space, an electrical pulse generator implantedin the lower abdominal area or gluteal region, and conducting wirescoupling the stimulating electrodes to the generator.

What is claimed is:
 1. A neurostimulation system, comprising: anelectrode assembly; and a neurostimulator coupled to the electrodeassembly, the neurostimulator comprising: a control circuit; and amemory operably coupled to the control circuit and comprisinginstructions that, when executed by the control circuit, cause thecontrol circuit to: deliver a first plurality of stimulation signalshaving a first frequency to a patient via the electrode assembly; detecta transition heart rate response corresponding to a neural fulcrum zoneresponsive to a first subset of the first plurality of stimulationsignals, the transition heart rate response being between a heart rateassociated with a tachycardia condition and a heart rate associated witha bradycardia condition; detect that delivering the first subset ofstimulation signals does not produce a predetermined level of change inthe heart rate of the patient; deliver a second plurality of stimulationsignals having a second frequency to the patient via the electrodeassembly, the second frequency being greater than the first frequency;detect the transition heart rate response corresponding to the neuralfulcrum zone responsive to a second subset of the second plurality ofstimulation signals; detect that delivering the second subset ofstimulation signals does produce the predetermined level of change inthe heart rate of the patient; and deliver the second subset ofstimulation signals to the patient via the electrode assembly.
 2. Theneurostimulation system of claim 1, wherein each of the first pluralityof stimulation signals comprises an output current amplitude, a pulsewidth, a duty cycle, and the first frequency; and wherein each of thesecond plurality of stimulation signals comprises an output currentamplitude, a pulse width, a duty cycle, and the second frequency.
 3. Theneurostimulation system of claim 1, wherein the instructions cause thecontrol circuit to: deliver the first plurality of stimulation signalshaving the first frequency by increasing an intensity of the firstplurality of stimulation signals from one signal to a next signal; anddetect the transition heart rate response responsive to the first subsetof the first plurality of stimulation signals based on the increase ofthe intensity of the first plurality of stimulation signals from onesignal to the next signal.
 4. The neurostimulation system of claim 3,wherein the instructions cause the control circuit to increase theintensity of the first plurality of stimulation signals from one signalto the next signal by increasing at least one of an output currentamplitude, a pulse width, or a duty cycle from one signal to the nextsignal.
 5. The neurostimulation system of claim 3, wherein theinstructions cause the control circuit to: deliver the second pluralityof stimulation signals having the second frequency by increasing anintensity of the second plurality of stimulation signals from one signalto a next signal; and detect the transition heart rate responseresponsive to the second subset of the second plurality of stimulationsignals based on the increase of the intensity of the second pluralityof stimulation signals from one signal to the next signal.
 6. Theneurostimulation system of claim 5, wherein the instructions cause thecontrol circuit to increase the intensity of the second plurality ofstimulation signals from one signal to the next signal by increasing atleast one of an output current amplitude, a pulse width, or a duty cyclefrom one signal to the next signal.
 7. The neurostimulation system ofclaim 1, wherein the transition heart rate response is a 0% to 5% heartrate reduction from a baseline heart rate.
 8. A method of operating aneurostimulator coupled to an electrode assembly, comprising: deliveringa first plurality of stimulation signals having a first frequency to apatient via the electrode assembly; detecting a transition heart ratresponse corresponding to a neural fulcrum zone responsive to a firstsubset of the first plurality of stimulation signals, the transitionheart rate response being between a heart rate associated with atachycardia condition and a heart rate associated with a bradycardiacondition; detecting that delivering the first subset of stimulationsignals does not produce a predetermined level of change in the heartrate of the patient; delivering a second plurality of stimulationsignals having a second frequency to the patient via the electrodeassembly, the second frequency being greater than the first frequency;detecting the transition heart rate response corresponding to the neuralfulcrum zone responsive to a second subset of the second plurality ofstimulation signals; detecting that delivering the second subset ofstimulation signals does produce the predetermined level of change inthe heart rate of the patient; and delivering the second subset ofstimulation signals to the patient via the electrode assembly.
 9. Themethod of claim 8, wherein each of the first plurality of stimulationsignals comprises an output current amplitude, a pulse width, a dutycycle, and the first frequency; and wherein each of the second pluralityof stimulation signals comprises an output current amplitude, a pulsewidth, a duty cycle, and the second frequency.
 10. The method of claim8, wherein delivering the first plurality of stimulation signals havingthe first frequency comprises increasing an intensity of the firstplurality of stimulation signals from one signal to a next signal; andwherein detecting the transition heart rate response responsive to thefirst subset of the first plurality of stimulation signals is based onincreasing the intensity of the first plurality of stimulation signalsfrom one signal to the next signal.
 11. The method of claim 10, whereinincreasing the intensity of the first plurality of stimulation signalsfrom one signal to the next signal comprises increasing at least one ofan output current amplitude, a pulse width, or a duty cycle from onesignal to the next signal.
 12. The method of claim 10, whereindelivering the second plurality of stimulation signals having the secondfrequency comprises increasing an intensity of the second plurality ofstimulation signals from one signal to a next signal; and whereindetecting the transition heart rate response responsive to the secondsubset of the second plurality of stimulation signals is based onincreasing the intensity of the second plurality of stimulation signalsfrom one signal to the next signal.
 13. The method of claim 12, whereinincreasing the intensity of the second plurality of stimulation signalsfrom one signal to the next signal comprises increasing at least one ofan output current amplitude, a pulse width, or a duty cycle from onesignal to the next signal.
 14. The method of claim 8, wherein thetransition heart rate response is a 0% to 5% heart rate reduction from abaseline heart rate.
 15. A memory coupled to a processor and comprisinginstructions that, when executed by the processor, cause the processorto: deliver a first plurality of stimulation signals having a firstfrequency to a patient via an electrode assembly; detect a transitionheart rate response corresponding to a neural fulcrum zone responsive toa first subset of the first plurality of stimulation signals, thetransition heart rate response between a heart rate associated with abradycardia condition; detect that delivering the first subset ofstimulation signals does not produce a predetermined level of change inthe heart rate of the patient; deliver a second plurality of stimulationsignals having a second frequency to the patient via the electrodeassembly, the second frequency being greater than the first frequency;detect the transition heart rate response corresponding to the neuralfulcrum zone responsive to the second subset of the second plurality ofstimulation signals; detect that delivering the second subset ofstimulation signals does produce the predetermined level of change inthe heart rate of the patient; and deliver the second subset ofstimulation signals to the patient via the electrode assembly.
 16. Thememory of claim 15, wherein each of the plurality of stimulation signalscomprises an output current amplitude, a pulse width, a duty cycle, andthe first frequency; and wherein each of the second plurality ofstimulation signals comprises an output current amplitude, a pulsewidth, a duty cycle, and the second frequency.
 17. The memory of claim15, wherein the instructions cause the processor to: deliver the firstplurality of stimulation signals having the first frequency byincreasing an intensity of the first plurality of stimulation signalsfrom one signal to a next signal; and detect the transition heart rateresponse responsive to the first subset of the first plurality ofstimulation signals based on the increase of the intensity of the firstplurality of stimulation signals from one signal to the next signal. 18.The memory of claim 17, wherein the instructions cause the processor toincrease the intensity of the first plurality of stimulation signalsfrom one signal to the next signal by increasing at least one of anoutput current amplitude, a pulse width, or a duty cycle from one signalto the next signal.
 19. The memory of claim 17, wherein the instructionscause the processor to: deliver the second plurality of stimulationsignals having the second frequency by increasing an intensity of thesecond plurality of stimulation signals from one signal to a nextsignal; and detect the transition heart rate response responsive to thesecond subset of the second plurality of stimulation signals based onthe increase of the intensity of the second plurality of stimulationsignals from one signal to the next signal.
 20. The memory of claim 15,wherein the transition heart rate response is a 0% to 5% heart ratereduction from a baseline heart rate.